Origin of Interstitial Fibroblasts in an Accelerated Model of Angiotensin II-Induced Renal Fibrosis

Faulkner, Jennifer L.; Szcykalski, Lisa M.; Springer, Fredyne; Barnes, Jeffrey L.

doi:10.1016/s0002-9440(10)61208-4

Cited by 96 publications

(92 citation statements)

References 49 publications

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“…However, it should be noted that activated resident interstitial fibroblasts may not be the only cells participating in extracellular matrix production. There have been reports that bone marrow-derived cells (39,40), transdifferentiated tubular epithelial and endothelial cells [via epithelial-to-mesenchymal (EMT) (39,41) and endothelial-tomesenchymal (EndMT) transition (4), respectively], and periadventitial cells (42,43) could also contribute to the population of interstitial matrix-producing cells in renal fibrotic disease.…”

Section: Discussionmentioning

confidence: 99%

Renal fibrosis is attenuated by targeted disruption of K _Ca 3.1 potassium channels

Grgic

Kiss

Kaistha

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

147

137

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Proliferation of interstitial fibroblasts is a hallmark of progressive renal fibrosis commonly resulting in chronic kidney failure. The intermediate-conductance Ca 2+ -activated K + channel (K Ca 3.1) has been proposed to promote mitogenesis in several cell types and contribute to disease states characterized by excessive proliferation. Here, we hypothesized that K Ca 3.1 activity is pivotal for renal fibroblast proliferation and that deficiency or pharmacological blockade of K Ca 3.1 suppresses development of renal fibrosis. We found that mitogenic stimulation up-regulated K Ca 3.1 in murine renal fibroblasts via a MEK-dependent mechanism and that selective blockade of K Ca 3.1 functions potently inhibited fibroblast proliferation by G 0 /G 1 arrest. Renal fibrosis induced by unilateral ureteral obstruction (UUO) in mice was paralleled by a robust up-regulation of K Ca 3.1 in affected kidneys. Mice lacking K Ca 3.1 (K Ca 3.1 −/− ) showed a significant reduction in fibrotic marker expression, chronic tubulointerstitial damage, collagen deposition and αSMA + cells in kidneys after UUO, whereas functional renal parenchyma was better preserved. Pharmacological treatment with the selective K Ca 3.1 blocker TRAM-34 similarly attenuated progression of UUO-induced renal fibrosis in wild-type mice and rats. In conclusion, our data demonstrate that K Ca 3.1 is involved in renal fibroblast proliferation and fibrogenesis and suggest that K Ca 3.1 may represent a therapeutic target for the treatment of fibrotic kidney disease.

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Section: Discussionmentioning

confidence: 99%

Renal fibrosis is attenuated by targeted disruption of K _Ca 3.1 potassium channels

Grgic

Kiss

Kaistha

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

147

137

View full text Add to dashboard Cite

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“…11,24 Male C57BL/6 mice (6 weeks old) were injected via tail vein with 0.2 mg Texas Red-dextran (3000 MW, Invitrogen) in 0.2 ml PBS. UUO or sham-operation was performed 48 hours later, and kidneys were harvested 3 to 14 days after surgery.…”

Section: In Vivo Labeling Of Proximal Tubular Cells With Fluorescent mentioning

confidence: 99%

“…10 -12 In a rat model of angiotensin II-induced renal fibrosis, fibroblasts originate from encroachment of interstitial myofibroblasts from the perivascular space rather than via EMT. 11 To further evaluate the role of EMT in nephron loss in obstructive uropathy, we performed lineage analysis using genetically modified mice in which epithelial cells of the proximal and distal nephron were labeled and cell fate was followed.…”

mentioning

confidence: 99%

Autophagy Is a Component of Epithelial Cell Fate in Obstructive Uropathy

Zepeda‐Orozco

Black

et al. 2010

The American Journal of Pathology

173

162

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Epithelial cell fate and nephron loss in obstructive uropathy are not fully understood. We produced transgenic mice in which epithelial cells in the nephrons and collecting ducts were labeled with enhanced yellow fluorescent protein, and tracked the fate of these cells following unilateral ureteral obstruction (UUO). UUO led to a decrease in the number of enhanced yellow fluorescent protein-expressing cells and down-regulation of epithelial markers, Ecadherin, and hepatocyte nuclear factor-1␤. Following UUO, enhanced yellow fluorescent protein-positive cells were confined within the tubular basement membrane, were not found in the renal interstitium, and did not express ␣-smooth muscle actin or S100A4, markers of myofibroblasts and fibroblasts. Moreover, when proximal tubules were labeled with dextran before UUO, dextran-retaining cells did not migrate into the interstitium or express ␣-smooth muscle actin. These results indicate that UUO leads to tubular epithelial loss but does not cause epithelial-tomesenchymal transition that has been shown by others to be responsible for nephron loss and interstitial fibrosis. For the first time, we found evidence of enhanced autophagy in obstructed tubules, including accumulation of autophagosomes, increased expression of Beclin 1, and increased conversion of microtubular-associated protein 1 light chain 3-I to -II. Increased autophagy may represent a mechanism of tubular survival or may contribute to excessive cell death and tubular atrophy after obstructive injury.

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“…28 Although the role of myofibroblasts in renal fibrosis is widely accepted, their origin and fate are still debated. 19,29 Recently, it has been shown that kidney tubular epithelial cells acquire mesenchymal features in response to TGF-␤1, but they accompanied no de novo expression of ␣-SMA. 30 Thus, TGF-␤1 does not necessarily induce myofibroblast transdifferentiation in a certain cell types including the PCK cholangiocytes, and in these cell lines TGF-␤1 may act as an inducer initiating a cascade of dedifferentiating events.…”

Section: Sato Et Almentioning

confidence: 99%

Cholangiocytes with Mesenchymal Features Contribute to Progressive Hepatic Fibrosis of the Polycystic Kidney Rat

Sato

Harada

Ozaki

et al. 2007

The American Journal of Pathology

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The polycystic kidney (PCK) rat is an animal model of Caroli's disease with congenital hepatic fibrosis, in which the mechanism of progressive hepatic fibrosis remains unknown. This study aimed to clarify the mechanism of hepatic fibrosis of the PCK rat from the viewpoint of the contribution of pathological cholangiocytes. In liver sections of the PCK rats, intrahepatic bile ducts were constituted by two different phenotypes: bile ducts lined by cuboidal-shaped and flat-shaped cholangiocytes. The flat-shaped cholangiocytes showed reduced immunohistochemical expression of the biliary epithelial marker cytokeratin 19 and positive immunoreactivity for vimentin and fibronectin. When cultured cholangiocytes of the PCK rat were treated with transforming growth factor (TGF)-␤1, a potent inducer of epithelial-mesenchymal transition, induction of vimentin, fibronectin, and collagen expression occurred in the PCK cholangiocytes. Although the TGF-␤1 treatment reduced cytokeratin 19 expression, the epithelial cell features characterized by the expression of E-cadherin and zonula occludens-1 was maintained, and ␣-smooth muscle actin expression was not induced in the cholangiocytes. Cholangiocytes of the PCK rat may acquire mesenchymal features in response to TGF-␤1 and participate in progressive hepatic fibrosis by producing extracellular matrix molecules, which seems to be a different event from epithelial-mesenchymal transition.

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Origin of Interstitial Fibroblasts in an Accelerated Model of Angiotensin II-Induced Renal Fibrosis

Cited by 96 publications

References 49 publications

Renal fibrosis is attenuated by targeted disruption of K _Ca 3.1 potassium channels

Renal fibrosis is attenuated by targeted disruption of K _Ca 3.1 potassium channels

Autophagy Is a Component of Epithelial Cell Fate in Obstructive Uropathy

Cholangiocytes with Mesenchymal Features Contribute to Progressive Hepatic Fibrosis of the Polycystic Kidney Rat

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Origin of Interstitial Fibroblasts in an Accelerated Model of Angiotensin II-Induced Renal Fibrosis

Cited by 96 publications

References 49 publications

Renal fibrosis is attenuated by targeted disruption of K Ca 3.1 potassium channels

Renal fibrosis is attenuated by targeted disruption of K Ca 3.1 potassium channels

Autophagy Is a Component of Epithelial Cell Fate in Obstructive Uropathy

Cholangiocytes with Mesenchymal Features Contribute to Progressive Hepatic Fibrosis of the Polycystic Kidney Rat

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Renal fibrosis is attenuated by targeted disruption of K _Ca 3.1 potassium channels

Renal fibrosis is attenuated by targeted disruption of K _Ca 3.1 potassium channels